Individual neurons have been shown to homeostatically alter the strength of their excitatory connections in response to network activity: chronic inactivity induces compensatory increases in synaptic efficacy, while chronic hyperactivity induces compensatory decreases in synaptic efficacy. In fact, the negative feedback loops of homeostatic synaptic plasticity (HSP) are thought to be essential for the stability of neurons and neural networks. However, associative, or Hebbian, synaptic plasticity, which is thought to underlie learning and memory, is proposed to proceed via positive feedback-based changes in synaptic strength. It is therefore unclear how homeostatic synaptic adaptation can occur in established neuronal networks without threatening Hebbian information storage. Using both morphological and functional analysis, we have observed that HSP in mature hippocampal neurons in vitro occurred preferentially at proximal synapses. The mechanism of proximal adaptation consisted of the activity-dependent formation and elimination of large, multi-lobed dendritic spines which morphologically, biochemically, and pharmacologically resemble thorny excrescences. Thorny excrescences, the complex proximal spines of CA3 pyramidal neurons in vivo, receive innervation from equally large presynaptic dentate gyrus (DG) mossy fiber terminals. The precise function of the highly specialized synapses between DG and CA3 neurons has remained enigmatic since their discovery over a century ago. We hypothesize that these synapses are the homeostatic gain control locus for not only mature hippocampal CA3 neurons, but for intact hippocampal networks. We therefore propose to investigate whether homeostatic synaptic adaptation occurs preferentially at mossy fiber-CA3 synapses. We will use a two-pronged functional and morphological approach to test this hypothesis both in vitro and in vivo. PUBLIC HEALTH RELEVANCE: The notion of homeostatic regulation, which ushered in the era of modern physiology, has only been applied to the central nervous system within the last 15 years and still has great potential to influence our approach to neurological disorders and dysfunction. We propose that homeostatic regulation of hippocampal circuits occurs at a specific location, namely the large, specialized synapses between dentate gyrus (DG) granule cells and CA3 pyramidal neurons. Intriguingly, this region has been extensively implicated in epileptogenesis, raising the possibility that our proposed studies will shed light on both the normal homeostatic regulation of hippocampal circuits and the pathogenesis of their disregulation in temporal lobe epilepsy and neurodegeneration.